Bridging in vitro buoyancy to clinical performance: A PBPK-driven analysis of once-daily Bepotastine gastro-retentive tablet in beagles and humans.

Bepotastine possesses a short half-life (∼2 h) and a narrow absorption window limited to the upper small intestine, necessitating a gastro-retentive drug delivery system for once-daily administration. In this study, we developed a low-density gastro-retentive tablet designed for instantaneous floating (zero lag time) to prevent premature gastric emptying-a critical limitation of conventional floating systems. This was achieved through a rational engineering approach using AutoCAD-based geometric integration to precisely control the initial apparent density below 1.004 g/cm3. The synergistic combination of low viscosity hypromellose (15 cP) and magnesium aluminometasilicate facilitated immediate buoyancy and sustained it for over 4 h through wicking-induced air entrapment and robust gel layer formation. In beagle dogs, the gastro-retentive tablet achieved 95.7% systemic exposure relative to a twice-daily reference, whereas non-floating sustained-release formulations reached only 64.5-88.6%, highlighting the necessity of gastric retention. Notably, a randomized clinical study in 28 healthy subjects confirmed that the scaled-up gastro-retentive formulation was bioequivalent to the reference product. Produced via standard manufacturing processes, the 100,000-tablet batch also demonstrated no clinically significant food effect. Species-specific physiologically based pharmacokinetic modeling mechanistically estimated gastric residence times of approximately 180 min in beagles and 360 min in humans, supporting the interpretation that the system may withstand multiple interdigestive migrating motor complex cycles. These findings validate the proposed gastro-retentive platform as a clinically viable, industrially scalable strategy for drugs with site-specific absorption.